Obesity-associated NLRC4 inflammasome activation drives breast cancer progression

Nat Commun. 2016 Oct 6;7:13007. doi: 10.1038/ncomms13007.

Abstract

Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Breast / metabolism
  • Breast Neoplasms / complications
  • Breast Neoplasms / metabolism*
  • CARD Signaling Adaptor Proteins / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Cell Line, Tumor / metabolism
  • Disease Progression
  • Female
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism*
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Mammary Neoplasms, Experimental / complications
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • Neoplasm Transplantation
  • Obesity / complications
  • Obesity / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Ipaf protein, mouse
  • NLRC4 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse